Browsing by Author "Charbe, Nitin B."

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    Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α
    (2020) Aljabali, Alaa A. A.; Bakshi, Hamid A.; Hakkim, Faruck L.; Haggag, Yusuf A.; Al-Batanyeh, Khalid M.; Al Zoubi, Mazhar S.; Al-Trad, Bahaa; Nasef, Mohamed M.; Satija, Saurabh; Mehta, Meenu; Pabreja, Kavita; Mishra, Vijay; Khan, Mohammed; Abobaker, Salem; Azzouz, Ibrahim M.; Dureja, Harish; Pabari, Ritesh M.; Dardouri, Ashref Ali K.; Kesharwani, Prashant; Gupta, Gaurav; Shukla, Shakti Dhar; Prasher, Parteek; Charbe, Nitin B.; Negi, Poonam; Kapoor, Deepak N.; Chellappan, Dinesh Kumar; da Silva, Mateus Webba; Thompson, Paul; Dua, Kamal; McCarron, Paul; Tambuwala, Murtaza M.
    Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC-BSA nanoparticles (NPs). These PIC-BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1 alpha. Our results indicate that PIC-BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1 alpha in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC-BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC-BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC-BSA NPs, enhances its therapeutic potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possible human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients.
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    Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage
    (2020) Bakshi, Hamid A.; Al Zoubi, Mazhar S.; Faruck, Hakkim L.; Aljabali, Alaa A. A.; Rabi, Firas A.; Hafiz, Amin A.; Al-Batanyeh, Khalid M.; Al-Trad, Bahaa; Ansari, Prawej; Nasef, Mohamed M.; Charbe, Nitin B.; Satija, Saurabh; Mehta, Meenu; Mishra, Vijay; Gupta, Gaurav; Abobaker, Salem; Negi, Poonam; Azzouz, Ibrahim M.; Dardouri, Ashref Ali K.; Dureja, Harish; Prasher, Parteek; Chellappan, Dinesh K.; Dua, Kamal; Da Silva, Mateus Webba; El Tanani, Mohamed; McCarron, Paul A.; Tambuwala, Murtaza M.
    Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.
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    Dynamics of Prolyl Hydroxylases Levels During Disease Progression in Experimental Colitis
    (2019) Bakshi, Hamid A.; Mishra, Vijay; Satija, Saurabh; Mehta, Meenu; Hakkim, Faruk L.; Kesharwani, Prashant; Dua, Kamal; Chellappan, Dinesh K.; Charbe, Nitin B.; Shrivastava, Garima; Rajeshkumar, S.; Aljabali, Alaa A.; Al-Trad, Bahaa; Pabreja, Kavita; Tambuwala, Murtaza M.
    Hypoxia inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitors are shown to be protective in several models of inflammatory bowel disease (IBD). However, these non-selective inhibitors are known to inhibit all the three isoforms of PHD, i.e. PHD-1, PHD-2 and PHD-3. In the present report, we investigated the associated changes in levels of PHDs during the development and recovery of chemically induced colitis in mice. The results indicated that in the experimental model of murine colitis, levels of both, PHD-1 and PHD-2 were found to be increased with the progression of the disease; however, the level of PHD-3 remained the same in group of healthy controls and mice with colitis. Thus, the findings advocated that inhibitors, which inhibited all three isoforms of PHD could not be ideal therapeutics for IBD since PHD-3 is required for normal gut function. Hence, this necessitates the development of new compounds capable of selectively inhibiting PHD-1 and PHD-2 for effective treatment of IBD.
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    Emergence of three dimensional printed cardiac tissue: opportunities and challenges in cardiovascular diseases
    (2019) Charbe, Nitin B.; Zacconi, Flavia C. M.; Amnerkar, Nikhil; Pardhi, Dinesh; Shukla, Priyank; Mukattash, Tareq L.; McCarron, Paul A.; Tambuwala, Murtaza M.
    Three-dimensional (3D) printing, also known as additive manufacturing, was developed originally for engineering applications. Since its early advancements, there has been a relentless development in enthusiasm for this innovation in biomedical research. It allows for the fabrication of structures with both complex geometries and heterogeneous material properties. Tissue engineering using 3D bio-printers can overcome the limitations of traditional tissue engineering methods. It can match the complexity and cellular microenvironment of human organs and tissues, which drives much of the interest in this technique. However, most of the preliminary evaluations of 3Dprinted tissues and organ engineering, including cardiac tissue, relies extensively on the lessons learned from traditional tissue engineering. In many early examples, the final printed structures were found to be no better than tissues developed using traditional tissue engineering methods. This highlights the fact that 3D bio-printing of human tissue is still very much in its infancy and more work needs to be done to realise its full potential. This can be achieved through interdisciplinary collaboration between engineers, biomaterial scientists and molecular cell biologists. This review highlights current advancements and future prospects for 3D bio-printing in engineering ex vivo cardiac tissue and associated vasculature, such as coronary arteries. In this context, the role of biomaterials for hydrogel matrices and choice of cells are discussed. 3D bio-printing has the potential to advance current research significantly and support the development of novel therapeutics which can improve the therapeutic outcomes of patients suffering fatal cardiovascular pathologies.
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    Hetero-substituted sulfonamido-benzamide hybrids as glucokinase activators: Design, synthesis, molecular docking and in-silico ADME evaluation
    (2020) Khadse, Saurabh C.; Amnerkar, Nikhil D.; Dighole, Krushna S.; Dhote, Ashish M.; Patil, Vikas R.; Lokwani, Deepak K.; Ugale, Vinod G.; Charbe, Nitin B.; Chatpalliwar, Vivekanand A.
    A series of hetero-substituted sulphonamido-benzamide derivatives which can activate glucokinase (GK) were synthesized and screened in-vitro using Human GK activation assay and in-vivo following oral glucose tolerance test (OGIT) assays. All the molecules were docked into the active site of 1V4S receptor grid by XP docking method utilizing Schrodinger software to assess the binding interactions. Compounds 12 (EC50 = 495 nM) and 15 (EC50 = 522 nM), revealed maximum in-vitro GK activation. Selected compounds were subjected for in-vivo OGIT assay. The data revealed that same compounds 12 (135 mg/dL) showed maximum reduction in blood glucose level followed by compound 15 (142 mg/dL) at 120 min. The docking results as glide score, binding energy and interactions were reported and compounds with maximum pharmacological activity were studied precisely. In-silico ADME parameters, pharmacokinetic properties and toxicity studies were carried out and all compounds were found to have good bioavailability and nontoxic. Overall, the series of hetero-substituted sulphonamido-benzamide hybrids are safe and could be explored further for better therapeutic efficacy as GK activators. (C) 2020 Elsevier B.V. All rights reserved.
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    Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression
    (Bentham Science Publ. LTD, 2021) Satija, Saurabh; Kaur, Harpreet; Tambuwala, Murtaza M.; Sharma, Prabal; Vyas, Manish; Khurana, Navneet; Sharma, Neha; Bakshi, Hamid A.; Charbe, Nitin B.; Zacconi, Flavia C. M.; Aljabali, Alaa A.; Nammi, Srinivas; Dureja, Harish; Singh, Thakur G.; Gupta, Gaurav; Dhanjal, Daljeet S.; Dua, Kamal; Chellappan, Dinesh K.; Mehta, Meenu
    Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1 beta (constitutive) and HIF-1 alpha (inducible). The HIF-1 alpha expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.
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    Perfluorocarbons Therapeutics in Modern Cancer Nanotechnology for Hypoxia-induced Anti-tumor Therapy
    (2021) Satija, Saurabh; Sharma, Prabal; Kaur, Harpreet; Dhanjal, Daljeet S.; Chopra, Reena S.; Khurana, Navneet; Vyas, Manish; Sharma, Neha; Tambuwala, Murtaza M.; Bakshi, Hamid A.; Charbe, Nitin B.; Zacconi, Flavia C. M.; Chellappan, Dinesh K.; Dua, Kamal; Mehta, Meenu
    With an estimated failure rate of about 90%, immunotherapies that are intended for the treatment of solid tumors have caused an anomalous rise in the mortality rate over the past decades. It is apparent that resistance towards such therapies primarily occurs due to elevated levels of HIF-1 (Hypoxia-induced factor) in tumor cells, which are caused by disrupted microcirculation and diffusion mechanisms. With the advent of nanotechnology, several innovative advances were brought to the fore; and, one such promising direction is the use of perfluorocarbon nanoparticles in the management of solid tumors. Perfluorocarbon nanoparticles enhance the response of hypoxia-based agents (HBAs) within the tumor cells and have been found to augment the entry of HBAs into the tumor micro-environment. The heightened penetration of HBAs causes chronic hypoxia, thus aiding in the process of cell quiescence. In addition, this technology has also been applied in photodynamic therapy, where oxygen self-enriched photosensitizers loaded perfluorocarbon nanoparticles are employed. The resulting processes initiate a cascade, depleting tumour oxygen and turning it into a reactive oxygen species eventually to destroy the tumour cell. This review elaborates on the multiple applications of nanotechnology based perfluorocarbon formulations that are being currently employed in the treatment of tumour hypoxia.
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    Quinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and in-silico ADMET prediction
    (2019) Khadse, Saurabh C.; Amnerkar, Nikhil D.; Dave, Manasi U.; Lokwani, Deepak K.; Patil, Ravindra R.; Ugale, Vinod G.; Charbe, Nitin B.; Chatpalliwar, Vivekanand A.
    Background A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and pi-pi interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.